alpha-Thrombin inhibits signal transducers and activators of transcription 3 signaling by interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor in CCL39 cells.
We recently demonstrated that, in rat aortic smooth muscle cells, alpha-thrombin stimulated Stat3/SIF-A (signal transducers and activators of transcription 3/sis-inducing factor-A) activity [G. J. Bhat et al. (1997) Hypertension 29(Pt. 2), 356-360]. In the present study, we observed that exposure of CCL39 cells (a Chinese hamster lung fibroblast cell line) to alpha-thrombin resulted in a time-dependent decrease in basal SIF-A activity. We hypothesized that the decrease in basal SIF-A was due to the initiation of an inhibitory pathway, following alpha-thrombin exposure. To test this hypothesis, we determined if alpha-thrombin would inhibit Stat3 and SIF-A activation by interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF). In support of this hypothesis, alpha-thrombin inhibited the Stat3/SIF-A response induced by all the above cytokines. The inhibition by alpha-thrombin was concentration dependent, was sensitive to hirudin, and was mimicked by the thrombin receptor agonist peptide. The inhibition did not require the activation of phorbol 12-myristate 13-acetate-sensitive isoforms of protein kinase C and was reversed by pretreatment with the mitogen-activated protein kinase kinase 1 (MAPKK1 or MEK1) inhibitor PD98059. Inhibitory cross talk between alpha-thrombin and IL-6 was also observed in MRC-5 cells, a fibroblast cell line derived from human lung tissue. Thus, we identify a novel alpha-thrombin inhibitory pathway which, acting through a MAPKK1-dependent mechanism, blocks IL-6-, LIF-, and CNTF-induced Stat3/SIF-A activation. This inhibitory cross talk may provide an important regulatory function to modulate gene transcription by these cytokines, during immune and inflammatory responses.
Bhat
G J
GJ
Research Program, Sigfried and Janet Weis Center for Research, The Pennsylvania State University College of Medicine, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA.
Hunt
R A
RA
Baker
K M
KM
D000818:Animals; D002460:Cell Line; D020934:Ciliary Neurotrophic Factor; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*
D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D004268:DNA-Binding Proteins; D005419:Flavonoids; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one